Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases affect the increasing aging populations worldwide. Disruption of lysosomal functions has been identified to be associated with these diseases. At least 11 genes out of 24 loci identified to be associated with Parkinson's disease are involved in or disrupt the autophagy-lysosome pathway. Our long term objective is to understand how lysosomes play an important role in clearance of excessive or toxic proteins and organelles and their potential as targets for therapeutic intervention for the treatment of neurodegenerative diseases. A key therapeutic strategy is to develop approaches to decrease pathogenic protein toxicity and spreading. This application will specifically test the hypothesis that strategies that enhance lysosomal function decrease pathogenic ?-synuclein burden and neurodegeneration in vivo. Novel genetic interventions that enhance lysosomal activities will be used to focus on rigorously examining 1) neurological deficit, 2) ?-synuclein accumulation and 3) neurodegeneration, in mice injected with preformed fibrils. Success of this study may provide long lasting impact regarding how lysosomal functions may be affected by a transcription repressor and a specific lysosomal enzyme, and regarding how lysosomal regulators and enzymes affect neuronal function and survival.